Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s amendments and remarks, filed 09/10/2025, are acknowledged.
Claims 29 and 35-37 are canceled.
Claims 1-2, 7, 28, 38, and 40 are amended.
Claims 1-28, 30-34, and 38-44 are pending.
As such, claims 1-28, 30-34, and 38-44 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/10/2025 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/10/2025 was filed after the mailing date of the final Office Action mailed on 03/10/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Withdrawn Objections
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 09/10/2025.
The specification objections are withdrawn. Issues regarding minor informalities and trademarks/names have been sufficiently addressed through amendments to the specification on 09/10/2025.
Withdrawn Rejections
Applicant’s arguments, see pages 12-35, filed 09/10/2025, with respect to claims 1, 2, 6, 15-16, 19-28, 30-33, 38, 40, and 43 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive in part. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Specifically, Examiner acknowledges that:
With respect to claim 2, Examiner acknowledges that STING proteins comprise a TRAF6 binding site. As such, the usage of “the TRAF6 binding site” has antecedent basis because the phrase is referencing the TRAF6 binding site in the STING protein.
With respect to claim 40, Examiner acknowledges that claim 40 now depends from claim 1.
Claim 1 was amended to recite “A modified Stimulator of Interferon Genes (STING) protein that is constitutively active so that (IFN) is constitutively expressed, and has lower activity, compared to the activity of human STING, wherein: the STING protein comprises amino acid modifications that result in the constitutive production of type I IFN; and the amino acid modifications comprise one or more of an amino acid insertion, deletion, and replacement”, thus removing the indefinite language.
With respect to claim 6, Examiner acknowledges that the art identifies what mutations of the STING protein (i.e., TMEM173 gene) that promotes interferonopathy; thus, one would understand what is encompassed by the limitation “a mutation that promotes an interferonopathy” of a STING protein.
With respect to claims 6, 15-16, and 43, Examiner acknowledges Applicant’s response regarding the phrases “by reference to” or “with reference to” are with respect to the SEQ ID Nos recited in the claims (i.e., SEQ ID Nos: 305-309).
With respect to claims 19 and 22, Examiner acknowledges that the term “delivery vehicle” is a relative term that is known in the art and in light of the present specification one would understand what is encompassed by the term in reference to the claimed invention.
With respect to claims 21-28, 30-32, and 38, Examiner acknowledges that the term “immunostimulatory bacteria” refers to therapeutic bacteria (bacteria that effect therapy, such as cancer or anti-tumor therapy, when administered to a subject, such as a human) that, when introduced into a subject, accumulate in immunoprivileged tissues and cells, such as tumors, and replicate and/or express products that are immunostimulatory or that result in immunostimulation (see pg. 34, lines 8-25). As such, it is clear what the term is encompassed.
With respect to claims 20 and 27, Examiner acknowledges that the Markush groupings recited in the claims share a common use and structure. Specifically, Examiner acknowledges that the Markush groupings of claim 20 each contain a nucleic acid that encode a payload and have a common use of a delivery vehicle; and, the Markush groupings of claim 27 are each proteins and have a common use of being immunostimulatory proteins.
With respect to claim 27, Examiner acknowledges that the cytoplasmic domain of a co-stimulatory receptor can be easily identified due to the structure of the co-stimulatory receptor. Further, Examiner acknowledges that the term “co-stimulatory” is an art-recognized term thus one would understand what a co-stimulatory protein or co-stimulatory receptor is and how they function.
With respect to claim 28, Examiner acknowledges that “IL-15/IL-15R alpha chain complex”, “members of the B7-CD28 family”, “proteins that are involved in or that effect or potentiate recruitment/persistence of T cells”, and “members of the tumor necrosis factor receptor (TNFR) superfamily” are art-recognized and one would know what members would be in the B7-CD28 family or TNFR superfamily and the structure of the IL-15/IL-15R alpha chain complex. Further, one would know what proteins that effect or potentiate recruitment/persistence of T cells.
Examiner acknowledges that claim 38 was amended to recite “pharmaceutically acceptable vehicle”.
As such, the above rejections under 35 USC 112(b) are withdrawn.
Applicant’s arguments, see pages 35-62, filed 09/10/2025, with respect to claims 13-14, 17, 39, and 41-44 rejected under 35 USC 112(a) as allegedly lacking written description have been fully considered and are persuasive. The issue regarding the specification failing to disclose Applicant’s possession of the large genus of modified STING proteins have been sufficiently addressed through amendments to the claims. Specifically, claims 13-14, 17, 39, and 41-44 provide sufficient description of the claimed modified STING proteins for one to determine its function (i.e., adequate structure-function correlation). As such, the rejection of claims 13-14, 17, 29, and 41-44 under 35 USC 112(a) is withdrawn.
Applicant’s arguments, see pages 66-71, filed 09/10/2025, with respect to claims 1-28, 30-33, and 38-43 provisionally rejected on the grounds of nonstatutory double patenting of copending Application No. 17/569,290 have been fully considered and are persuasive. Examiner acknowledges that copending application 17/569,290 was amended to recite a plasmid encoding a modified STING. Because the copending application is now drawn to nucleic acids, the present invention and copending invention are patentably distinct. As such, the provisional double patenting rejection of claims 1-28, 30-33, and 38-43 is withdrawn.
Applicant’s arguments, see pages 71-73, filed 09/10/2025, with respect to claims 1-28, 30-34, and 38-44 provisionally rejected on the grounds of nonstatutory double patenting of copending Application No. 17/320,200 have been fully considered and are persuasive. Examiner acknowledges that copending application 17/320,200 is drawn to an immunostimulatory bacterium comprising a plasmid encoding a modified STING. Because the copending application is drawn to nucleic acids, the present invention and copending invention are patentably distinct. As such, the provisional double patenting rejection of claims 1-28, 30-34, and 38-44 is withdrawn.
Applicant’s arguments, see pages 73 and 74, filed 09/10/2025, with respect to claims 1-28, 30-34, and 38-44 rejected on the grounds of nonstatutory double patenting of US Patent No. 12,024,709 have been fully considered and are persuasive. Examiner acknowledges that US Patent No. 12,024,709 is drawn to an immunostimulatory bacterium comprising a plasmid encoding a modified STING. Because the ‘709 patent is drawn to nucleic acids, the present invention and copending invention are patentably distinct. As such, the double patenting rejection of claims 1-28, 30-34, and 38-44 is withdrawn.
Applicant’s remarks, see pages 74-80, filed 09/10/2025, with respect to claims 1, 6, 15, and 18 rejected under 35 USC 102 as allegedly anticipated by Keskitalo et al. as evidenced by Trompouki et al. have been fully considered and are persuasive. Examiner acknowledges that the art does not disclose that the modified STING proteins comprising G207E mutations lowered NF-ĸB signaling pathway activity. As such, the rejection of claims 1, 6, 15, and 18 under 35 USC 102 is withdrawn.
Applicant’s remarks, see pages 80-96, filed 09/10/2025, with respect to claims 1, 6, 15, 16 and 18 rejected under 35 USC 103 as being unpatentable over Keskitalo et al., as evidenced by Trompouki et al., and further in view of Konno et al; claims 1, 6, 15, 16, 18, and 38 rejected under 35 USC 103 as being unpatentable over Keskitalo et al, as evidenced by Trompouki et al, Konno, and Fisher; and, claims 1-11, 13-18, and 38-43 rejected under 35 USC 103 as being unpatentable over Keskitalo et al, as evidenced by Trompouki et al, Konno, Miller et al, and de Oliveira Mann et al have been fully considered and are persuasive. Examiner acknowledges that Konno et al does not disclose that the modified STING proteins comprising G207E mutations lowered NF-ĸB signaling pathway activity. As such, the rejections under 35 USC 103 are withdrawn.
Claim Objections
Claims 6 and 38 objected to because of the following informalities:
Claim 6: “effected” should read “affected”.
Claim 38: “in pharmaceutically acceptable vehicle” should read “in a pharmaceutically acceptable vehicle”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 26-28, 34, and 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites “the C-terminal tail (CTT)” or “CTT”. These terms render the claim scope indefinite. The specification states that “As used herein, the "carboxy-terminal tail" or "C-terminal tail" (CTT) of the innate immune protein STING refers to the C-terminal portion of a STING protein that, in a wild-type STING protein, is tethered to the cGAMP-binding domain by a flexible linker region. The CTT includes an IRF3 binding site, a TBKI binding site, and a TRAF6 binding site.” However, the definition sets forth only function and undefined domains without defining the residues or consensus sequence within the CTT.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 26 recites the broad recitation “contributes to anti-tumor immunity in the tumor microenvironment”, and the claim also recites “confers anti-tumor immunity in the tumor microenvironment” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 27 recites the broad recitation “a co-stimulatory receptor”, and the claim also recites “a co-stimulatory receptor with the cytoplasmic domain deleted” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 28 recites the broad recitations “IL-2” , “IL-15” and “involved in or that effect”, and the claim also recites “IL-2 that has attenuated binding to IL-2Ra, IL-2 modified so that it does not bind to IL-2Ra”, “IL-15/IL-15R alpha chain complex”, and “potentiate”, respectively, which are the narrower statements of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 28 is indefinite because it recites the following limitation: “IL-2 that has attenuated binding to IL-2Ra” (see line 3). However, the specification does not provide guidance or a definition of the proteins encompassed by this term. The scope of the term is therefore indefinite.
Claim 28 is indefinite because it recites the following limitation: “IL-2 modified so that it does not bind to IL-2Ra” (see line 3-4). However, the specification does not provide guidance or a definition of the proteins encompassed by this term. The scope of the term is therefore indefinite.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 34 recites the broad recitation “a primary cell”, and the claim also recites “an immune cell, a stem cell, a tumor cell” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 40 recites “wherein the tumor necrosis factor receptor associated factor 6 (TRAF6) binding site of the STING protein is deleted”. It is unclear if “the TRAF6 binding site of the STING protein” is in reference to the modified STING protein or to the human STING that is being compared.
Applicant’s Arguments
Applicant requests reconsideration of the grounds for the rejections under 35 USC 112(b) (see pages 12-35 of the Remarks filed 09/10/2025).
With respect to the rejection of claims 2, 3, 7, 9, and 11-14, Applicant argues that claims are not read in a vacuum but instead are considered in light of the specification and the general understanding of the skilled artisan… As stated above and previously, STING domains were known to those of skill in the art prior to the filing date of the application. It should not be necessary to recite the domain structure of a STING protein in each claim when the domains of STING proteins are well known as described in the application and known in the art… The application, provides a definition of the "carboxy-terminal tail" of "C-terminal tail" (CTT) of STING, provides exemplary STING CTT sequences and the IRF3, TBK1 and TRAF6 binding sites in each of the CTT sequences… Applicant is not relying on the features in the CTT to define the CTT, but is providing evidence that the CTT is known in the art and one of skill in the art is able to determine the sequence of the CTT from any STING protein… One of skill in the art, in reading the specification and in view of the knowledge in the art, including protein databases, can readily determine the sequence of a CTT in a STING protein, including those from STING proteins with lower NF-ĸB signaling activity than human STING. The functional aspects of the CTT, described in the specification and above, evidence that one of skill in the art can identify the CTT of a STING protein. Thus, one skill in the art, light of the specification, and possession knowledge of the structure of STING proteins, understands what is meant by “the C-terminal tail (CTT)” or “CTT” as set forth in the application.
With respect to claim 26, Applicant argues that claim 26 recites, in the alternative, two effects of a further expressed immunostimulatory protein. There is no question or doubt with respect to broad and narrow range limitation because the claim recites alternative functional limitations as either conferring anti-tumor immunity in the tumor microenvironment or contributing to anti-tumor immunity in the tumor microenvironment. For the reasons stated above, the skilled person, having knowledge of cancer immunotherapy and immunostimulatory proteins, in light of the specification, understands the effects recited in the claim. Claim 26, thus, is clear. If necessary for allowance, Applicant will redraft the claim as two separate claims: one recited that the immunostimulatory protein confers anti-tumor immunity in the tumor microenvironment, and the other that recites that the immunostimulatory protein contributes to anti-tumor immunity.
With respect to claim 27, Applicant argues that claim 27 recites a list of products, i.e., immunostimulatory proteins including co- stimulatory molecules such as including co-stimulatory receptors. Co-stimulatory receptors are known in the art and describe a class of immunostimulatory proteins. Co-stimulatory receptors with the cytoplasmic domain deleted are a distinct subset of this set of proteins because the receptors are modified; the cytoplasmic domain of proteins is known and those of skill in the art can delete these domains accordingly… The skilled person, having knowledge of cancer immunotherapy and immunostimulatory proteins understands that "co-stimulatory receptor" and "co-stimulatory receptor with the cytoplasmic domain deleted" refer to separate co-stimulatory molecules. These terms do not constitute ranges of a protein, but refer to a protein, and to a modified protein with a particular domain deleted. One of skill in the art understands the metes and bounds of the claim.
With respect to claim 28, Applicant argues that the terms “IL-2 that has attenuated binding to IL-2Ra" and “IL-2 modified so that it does not bind to IL-2Ra” are art-recognized terms, and are known immunostimulatory proteins in the art… Applicant submits that the structure of the proteins is not necessary; these proteins are skill in the art of the bounds of the claimed invention and is as precise as the subject matter permits. Shatterproof Glass Corp. v. Libbey-Owens Ford Co., 758 F.2d 613, 624, 225 USPQ 634, 641 (Fed. Cir. 1985), cert. dismissed, 106 S.Ct. 340 (1985). Thus, these art-recognized terms and clear and do not render the claim indefinite.
With respect to claims 28 and 34 rejected for broad to narrow limitations within the claim, Applicant respectfully submits that the "broad to narrow" rejections are not applicable because the claims list distinct proteins (claim 28) or cells (claim 34). As described above, the proteins listed in claim 28 are distinct; the claim recites immunostimulatory proteins that are listed in the application and known in the art, including known modifications of the immunostimulatory proteins. There is no broad to narrow range between any of the recited proteins, as all are distinct. A primary cell is distinct from a stem cell, from a tumor cell, and from an immune cell. There is no broad to narrow range when the recited elements are distinct entities. Applicant respectfully submits that the claims are clear.
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive. Please note that the rejection of claim 40 is a new rejection necessitated by amendment; therefore, this rejection is not addressed below.
Examiner acknowledges the teachings of the specification regarding the CTT; however, Applicant is respectfully reminded the features upon which applicant relies (i.e., the CTT, in a wild-type STING, is tethered to the cGAMP-binding domain of STING by a flexible linker region) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Further, while dependent claims 11 and 12 do recite specific CTT sequences and their corresponding species, the remaining claims in the rejection do not recite specific sequences and simply just state language like “the C-terminal tail from a second species” which does not clearly describe what is encompassed by that structure, and only recites functional characteristics for which criteria to define said characteristics have not been presented in the instant specification or claims. One would not be reasonably apprised as to what CTT sequences from what species would be encompassed by the claims. For example, the specification does not provide criteria other than broadly-referenced functional aspects to define the domains within the CTT. Also, while claims 11 and 12 recite specific sequences, they only recite part of the full invention. These claims depend from claim 9 which is drawn to a STING protein chimera comprising sequences of two different species. Claim 11 is drawn to the “replacement CTT” sequences and claim 12 is drawn to the human STING CTT sequence. These claims only teach of one of the encompassed CTT species recited in claim 9. Lastly, Examiner respectfully disagrees with Applicant’s correlation with the present claims and the “modified car” analogy. The present claims are drawn to a large genus of CTT (STING) species that require a specific function (i.e., “has lower activation of the NF-ĸB signaling pathway compared to another STING species”), whereas Applicant’s analogy references a modified car comprising white leather seat upholstery. It is apparent that one would not need to recite that a car comprises seats because that is inherent that cars comprise seats. It is not inherent or clearly identifiable which STING species would have lower activation of the NF-ĸB signaling pathway compared to another STING species without identifying the two species to be compared. While Examiner agrees that the specification recites specific animal species in comparison to human STING, as stated above the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Thus, there remains uncertainty as to what is encompassed by the invention because the claims are not limited to the exemplary species recited in the specification.
With respect to claim 26, the limitations render the claim indefinite because while they recite alternative functional limitations, the limitation “contributing to” overlaps in scope the limitation “conferring to”. Examiner suggests amending the claim to two separate claims to overcome the rejection.
With respect to Applicant’s arguments for claim 27, Examiner respectfully disagrees. As stated by Applicant, a co-stimulatory receptor with the cytoplasmic domain deleted is a subset (i.e., species) of the genus of co-stimulatory receptors. As such, the recitation of “co-stimulatory receptors” is broader in scope compared to “a co-stimulatory receptor with the cytoplasmic domain deleted”. Examiner suggests amending the claim to two separate claims to overcome the rejection.
In regard to the terms "IL-2 that has attenuated binding to IL-2Ra” and "IL-2 modified so that it does not bind to IL-2Ra" being art-recognized terms and have been in issued patents, Applicant is reminded that each application is evaluated on a case-by-case basis using fact-specific inquiries. In this particular case, these terms are recited in the claims but there is no structure associated with them, thus one of skill in the art would not be apprised as to what is encompassed by these terms. These terms are solely described by function and do not provide a correlating structure that provides said result. Different animal species comprise of different IL-2 structures wherein different mutations will result in the present claimed functions. For example, Wang et al (Developmental and Comparative Immunology 115 (2021) 103895) recites different mutations that reduce or abolish IL-2 binding to IL-2Rα in fish (see page 10, right col.); and, Mott et al (J. Mol. Biol. (1995) 247, 979–994) and Dashwood et al (Computational and Structural Biotechnology Journal 27 (2025) 1112–1123) disclose of different mutations that reduce or abolish IL-2 binding to IL-2Rα in humans and mice (see page 982, left col. of Mott et al and Table 1 of Dashwood et al). In contrast, other mutations in the same domains may not result in the desired functions. These examples demonstrate that though IL-2 is conserved, multiple mutations can perform the claimed function thus one would not be apprised as to which species are encompassed by the limitations of the present claims.
With respect to claims 28 and 34, Examiner respectfully disagrees with Applicant’s assertion that there is no broad to narrow range between any of the recited proteins, as all are distinct. The recitation of “IL-2” , “IL-15” and “involved in or that effect” in claim 28 and “a primary cell” in claim 34 are broader in scope compared to “IL-2 that has attenuated binding to IL-2Ra” , IL-2 modified so that it does not bind to IL-2Ra”, “IL-15/IL-15R alpha chain complex”, “potentiate”, and “an immune cell, a stem cell, a tumor cell”, respectively, because the latter are all subsets (i.e., species) of the broader limitations. An IL-2 that has attenuated binding to IL-2Ra is still an IL-2, a protein that potentiates recruitment/persistence of T cells is still involved in or effects the recruitment/persistence of T cells, and a stem cell is a type of primary cell. As such, the claims are simply reciting a larger genus and their encompassed species.
As such, the 112(b) rejections are maintained.
Claim Rejections - 35 USC § 112(a) Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12, 14-16, 18-28, 30-34, 38, and 40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Claim 1 is drawn to a modified Stimulator of Interferon Genes (STING) protein that is constitutively active so that type I interferon (IFN) is constitutively expressed, and has lower nuclear factor kappa-light-chain- enhancer of activated B cell (NF-κB) signaling pathway activity, compared to the NF-κB signaling pathway activity of human STING, wherein: the STING protein comprises amino acid modifications that result in the constitutive production of type I IFN; and the amino acid modifications comprise one or more of an amino acid insertion, deletion, and replacement.
Claim 2 is drawn to the modified STING protein of claim 1 that is: a) a modified non-human STING protein, wherein the non-human STING protein has lower activation of the NF-κB signaling pathway than human STING, and the non-human STING comprises one or more amino acid modifications that result in constitutive production of type I interferon; or b) a chimeric STING protein comprising a first species STING protein with replacement of the C-terminal tail (CTT) from a second species STING protein, wherein the second species STING protein has lower activation of the NF-KB signaling pathway than the first species STING, and the chimeric STING protein comprises one or more amino acid modifications that result in constitutive production of type I interferon; or c) the non-human STING protein of a) or the chimeric STING protein of b) that has a deletion in the tumor necrosis factor receptor associated factor 6 (TRAF6) binding site; or d) a modified STING protein that comprises one or more amino acid modifications that result in constitutive production of type I interferon, and comprises a modification that removes a phosphorylation site, whereby the modified STING protein has lower activation of the NF-KB signaling pathway than unmodified human STING.
Claim 3 is drawn to the modified STING protein of claim 1 that is a chimeric STING that comprises a human STING in which the C-terminal tail (CTT) is replaced with a CTT from a non-human STING that has lower activation of the NF-κB signaling than human STING.
Claim 4 is drawn to the modified STING protein of claim 2, wherein the non-human species is selected from among Tasmanian devil, marmoset, cattle, cat, ostrich, boar, bat, manatee, crested ibis, coelacanth, and ghost shark.
Claim 5 is drawn to the modified STING protein of claim 3, wherein the non-human species is selected from among Tasmanian devil, marmoset, cattle, cat, ostrich, boar, bat, manatee, crested ibis, coelacanth, and ghost shark.
Claim 6 is drawn to the modified STING protein of claim 1, wherein the modification of STING is a mutation or mutations that correspond, by reference to and alignment with human STING, to a mutation that promotes an interferonopathy, wherein the sequence of human STING with which alignment is affected is set forth in any of SEQ ID NOs:305-309.
Claim 7 is drawn to the modified STING protein of claim 1 that is a chimeric STING protein, wherein: the chimeric STING protein comprises a portion of a human STING protein, and a C-terminal tail (CTT) from a non-human STING protein in place of the human CTT; the non-human STING protein has attenuated activation of the NF-κB signaling pathway, compared to the activation of the NF-κB signaling pathway of human STING; and the chimeric STING protein is constitutively active so that type I IFN is constitutively expressed.
Claim 8 is drawn to the modified STING protein of claim 2, wherein the unmodified STING protein is a human STING protein that comprises the sequence of amino acids set forth in any of SEQ ID Nos: 305-309, or is a human variant thereof with at least 98% sequence identity to the sequence of amino acids set forth in any of SEQ ID Nos: 305-309.
Claim 9 is drawn to the modified STING protein of claim 1, wherein: the STING protein is a chimera comprising replacement of a C-terminal tail (CTT) region in a STING protein from a first species with the CTT of a STING protein from a second species; the STING protein of the second species has lower activation of the NF-κB signaling pathway than the activation of the NF-κB signaling pathway of human STING; and the TRAF6 binding site in the CTT optionally is deleted.
Claim 10 is drawn to the modified STING protein of claim 9 that is a chimera comprising portions of STING proteins from two species, wherein the first species is human, and the second species is selected from among Tasmanian devil, marmoset, cattle, cat, ostrich, boar, bat, manatee, crested ibis, coelacanth, and ghost shark.
Claim 11 is drawn to the modified STING protein of claim 9, wherein the replacing CTT is selected from among the following species and has a sequence:
Tasmanian devil RQEEFAIGPKRAMTVTTSSTLSQEPQLLISGMEQPLSLRTDGF SEQ ID NO:353,
Marmoset EEEEVTVGSLKTSEVPSTSTMSQEPELLISGMEKPLPLRSDLF SEQ ID NO:354,
Cow EREVTMGSTETSVMPGSSVLSQEPELLISGLEKPLPLRSDVF SEQ ID NO:355,
Cat EREVTVGSVGTSMVRNPSVLSQEPNLLISGMEQPLPLRTDVF SEQ ID NO:356,
Ostrich RQEEYTVCDGTLCSTDLSLQISESDLPQPLRSDCL SEQ ID NO:357,
Boar EREVTMGSAETSVVPTSSTLSQEPELLISGMEQPLPLRSDIF SEQ ID NO:358,
Bat EKEEVTVGTVGTYEAPGSSTLHQEPELLISGMDQPLPLRTDIF SEQ ID NO:359,
Manatee EREEVTVGSVGTSVVPSPSSPSTSSLSQEPKLLISGMEQPLPLRTDVF SEQ ID NO:360,
Crested ibis CHEEYTVYEGNQPHNPSTTLHSTELNLQISESDLPQPLRSDCF SEQ ID NO:361,
Coelacanth (variant 1) QKEEYFMSEQTQPNSSSTSCLSTEPQLMISDTDAPHTLKRQVC SEQ ID NO:362,
Coelacanth (variant 2) QKEEYFMSEQTQPNSSSTSCLSTEPQLMISDTDAPHTLKSGF SEQ ID NO:363, and Ghost shark LTEYPVAEPSNANETDCMSSEPHLMISDDPKPLRSYCP SEQ ID NO: 365, or variants of each of these sequences having at least 98% sequence identity thereto.
Claim 12 is drawn to the modified STING protein of claim 9, wherein the human STING CTT comprises the sequence EKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS (SEQ ID NO:352), or is a variant having at least 98% sequence identity thereto.
Claim 14 is drawn to the modified STING protein of claim 1 that is a chimeric protein that comprises human STING with a CTT from Tasmanian Devil STING and an amino acid replacement in the human portion that confers constitutive production of type I IFN on the STING protein.
Claim 15 is drawn to the modified STING protein of claim 1, wherein the amino acid modification(s) that confer constitutive production of type I IFN is/are one or more amino acid replacements selected from replacements that correspond to S102P, V147L, V147M, N154S, V155M, G166E, C206Y, G207E, S102P/F279L, F279L, R281Q, R284G, R284S, R284M, R284K, R284T, R197A, D205A, R310A, R293A, T294A, E296A, R197A/D205A, S272A/Q273A, R310A/E316A, E316A, E316N, E316Q, S272A, R293A/T294A/E296A, D231A, R232A, K236A, Q273A, S358A/E360A/S366A, D231A/R232A/K236A/R238A, S358A, E360A, S366A, R238A, R375A, and S324A/S326A, with reference to the sequence of human STING, as set forth in any one of SEQ ID NOs:305-309.
Claim 16 is drawn to the modified STING protein of claim 1, comprising a replacement corresponding to C206Y or R284G, with reference to the sequence of human STING as set forth in any of SEQ ID NOs:305-309.
Claim 18 is drawn to the modified STING protein of claim 1, wherein the sequence of the unmodified STING protein comprises a sequence set forth in SEQ ID NOs: 305-309, 331, 338 and 341-350, or a sequence having at least 98% sequence identity to any of the STING proteins set forth in any of SEQ ID NOs: 305-309, 331, 338 and 341-350.
Claim 19 is drawn to a delivery vehicle, comprising the modified STING protein of claim 1.
Claim 20 is drawn to the delivery vehicle of claim 19 that is selected from among a nanoparticle, a liposome, an exosome, a bacterium, a virus, a cell, and a microvesicle.
Claim 21 is drawn to an immunostimulatory bacterium, comprising the modified STING protein of claim 1.
Claim 22 is drawn to the immunostimulatory bacterium of claim 21, wherein the bacterium comprises modification of the genome whereby Toll-Like Receptor 2 (TLR2), TLR4, and TLR5 recognition is reduced compared to the bacterium that does not have the genome modifications.
Claim 23 is drawn to the immunostimulatory bacterium of claim 21, wherein: the bacterium comprises genome modifications whereby the bacterium lacks flagella and comprises penta-acylated lipopolysaccharide; and the wild-type bacterium has flagella.
Claim 24 is drawn to the immunostimulatory bacterium of claim 21, wherein the bacterium comprises genome modifications whereby the bacterium is pagP-/msbB-.
Claim 25 is drawn to the immunostimulatory bacterium of claim 23, wherein the immunostimulatory bacterium comprises genome modifications whereby the bacterium is one or more of purl-, purD-, adrA-, csgD-, qseC-, hilA-, lppA-, and lppB-.
Claim 26 is drawn to the immunostimulatory bacterium of claim 21, that further comprises an immunostimulatory protein, that, when expressed in a mammalian subject, confers or contributes to anti-tumor immunity in the tumor microenvironment.
Claim 27 is drawn to the immunostimulatory bacterium of claim 26, wherein the immunostimulatory protein is one or more of a cytokine, a chemokine, a co-stimulatory protein, a co-stimulatory receptor, or a co-stimulatory receptor with the cytoplasmic domain deleted.
Claim 28 is drawn to the immunostimulatory bacterium claim 26, wherein the immunostimulatory protein is one or more of interleukin -2 (IL-2), IL-7, IL-12p70 (IL-12p40 + IL-12p35), IL- 15, IL-15/IL-15R alpha chain complex, IL-2 that has attenuated binding to IL-2Ra, IL-2 modified so that it does not bind to IL-2Ra, IL-18, IL-36 gamma, CXCL9, CXCL10, CXCL11, CCL3, CCL4, CCL5, proteins that are involved in or that effect or potentiate recruitment/persistence of T cells, CD40, CD40 Ligand (CD40L), OX40, OX40 Ligand (OX40L), 4-1BB, 4-1BB Ligand (4-1BBL), members of the B7-CD28 family, a TGF-beta polypeptide antagonist, and members of the tumor necrosis factor receptor (TNFR) superfamily.
Claim 30 is drawn to the immunostimulatory bacterium of claim 23, wherein the bacterium is a strain of Salmonella, Shigella, Escherichia coli, Bifidobacteriae, Rickettsia, Vibrio, Listeria, Klebsiella, Bordetella, Neisseria, Aeromonas, Francisella, Cholera, Corynebacterium, Citrobacter, Chlamydia, Haemophilus, Brucella, Mycobacterium, Mycoplasma, Legionella, Rhodococcus, Pseudomonas, Helicobacter, Bacillus, or Erysipelothrix, or an attenuated strain thereof or a modified strain thereof of any of the preceding list of bacterial strains.
Claim 31 is drawn to the immunostimulatory bacterium of claim 30 that is a strain of Salmonella.
Claim 32 is drawn to the immunostimulatory bacterium of claim 31 that is a Salmonella typhimurium strain.
Claim 33 is drawn to an isolated cell, comprising the delivery vehicle of claim 19.
Claim 34 is drawn to the cell of claim 33 that is an immune cell, a stem cell, a tumor cell, or a primary cell.
Claim 38 is drawn to a pharmaceutical composition, comprising the modified STING protein of claim 1 or comprising an immunostimulatory bacterium comprising the modified STING protein in an acceptable vehicle.
Claim 40 is drawn to the modified STING protein of claim 8, wherein the tumor necrosis factor receptor associated factor 6 (TRAF6) binding site is deleted.
The instant claims require a STING polypeptide that has the following required functions: that constitutively induces type I interferon; has attenuated nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling activity compared to the NF-κB signaling activity of human STING; a C-terminal tail (CTT) from a non-human STING protein wherein the non-human STING protein has lower NF-κB signaling activity than human STING; the TRAF6 binding site in the CTT is deleted; comprise portions of STING proteins from two species, whereby the resulting STING protein has constitutive IFN-beta signaling activity, wherein the first species is human, and the second species is selected from among Tasmanian devil, marmoset, cattle, cat, ostrich, boar, bat, manatee, crested ibis, coelacanth, and ghost shark; and confer constitutive activity is/are one or more amino acid replacements selected from replacements that correspond to S102P, V147L, V147M, N154S, V155M, G166E, C206Y, G207E, S102P/F279L, F279L, R281Q, R284G, R284S, R284M, R284K, R284T, R197A, D205A, R310A, R293A, T294A, E296A, R197A/D205A, S272A/Q273A, R310A/E316A, E316A, E316N, E316Q, S272A, R293A/T294A/E296A, D231A, R232A, K236A, Q273A, S358A/E360A/S366A, D231A/R232A/K236A/R238A, S358A, E360A, S366A, R238A, R375A, and S324A/S326A, with reference to the sequence of human STING, as set forth in any one of SEQ ID NOs:305-309.
The specification teach of auxotrophic strains of S. typhimurium (see Example 1); defects in intracellular replication are attributed to the msbB mutation (see Example 2); Salmonella asd gene knockout stain engineering and characterization (see Example 3); modified S. typhimurium strains with plasmids containing CpG elements demonstrate enhanced anti-tumor activity compared to the YS1646 parental strain (see Example 4); vector synthesis (see Example 5); S. typhimurium flagellin knockout by deletion of the fliC and fljB genes (see Example 6); S. typhimurium engineered to express cytoLLO for enhanced plasmid delivery (see Example 7); adenosine auxotrophic strains of S. typhimurium (see Example 8); characterization and use of the asd gene complementation system in vitro (see Example 9); exemplary strains engineered for increased tolerability (see Example 10); pagP deletion mutants have penta-acylated LPS and induce reduced inflammatory cytokines (see Example 11); FLG and PagP deletion mutants are more attenuated than YS1646 in mice (see Example 12); S. typhimurium immune modulator strains demonstrate expression of heterologous proteins in human monocytes (see Example 13); cell infection with ΔhilA mutant leads to less human epithelial cell infection (see Example 14); cell infection with ΔhilA or ΔfljB/ΔfliC mutants leads to less pyroptosis in human macrophages (see Example 15); infection of human macrophages with an immunostimulatory S. typhimurium stain containing a plasmid encoding an IL-2 expression cassette leads to secretion of IL-2 (see Example 16); S. typhimurium strains expressing murine IL-2 demonstrate potent tumor growth inhibition in vivo (see Example 17); Salmonella csgD gene knockout strain engineering and characterization (see Example 18); plasmid construction (see Example 19); identification of gain-of-function mutations in genes that promote interferonopathies (see Example 20); protein engineering screening to identify improved gain-of-function mutations in STING, RIG-I, MDA5, IRF3, IRF7, and other interferon pathway genes (see Example 21); transformation of plasmids encoding constitutively active immunostimulatory proteins into immunostimulatory bacterial strains (see Example 22); plasmids demonstrate expression of functional STING gain-of-function mutants in human cells (see Example 23); mSTING gain-of-function (GOF) encoding strains demonstrate significant anti-tumor activity in mice (see Example 24); systemically administered bacteria encoding a constitutively active STING variant inhibits growth of MC38 colon tumors in vivo (see Example 25); immunostimulatory bacteria encoding constitutively active STING variants stimulate enhanced expression from the interferon regulatory factor (IRF) promoter (see Example 26); immunostimulatory bacteria containing plasmids encoding constitutive type I IFN variants demonstrate potent anti-tumor immunity in a murine model of colorectal cancer (see Example 27); and, immunostimulatory bacteria modified to express vertebrate STING variants that induce stronger type I IFN signaling and/or weaker NF-κB signaling than human STING (see Example 28).
Particularly, the specification discloses that STING proteins from different species exhibit different levels of type I IFN and NF-κB signaling activities; for example, STING signaling in human and mouse cells results in a strong type I IFN response, and a weak pro-inflammatory NF-κB response (see pg. 268, lines 27-30). STING signaling in ray-finned fish, such as salmon and zebrafish, in comparison, elicits robust activation of a primarily NF-κB-driven response, that is more than 100-fold higher compared with the IRF3-driven (i.e., type I IFN inducing) response; in other species, such as Tasmanian devil, STING signaling results in a type I IFN response, but essentially no NF-κB response (see pg. 268-269). of modified STING variants wherein the highest type I IFN responses were observed from the variant in which the CTT of human STING was replaced with the CTT of Tasmanian devil STING, and that contained the human STING GOF mutation R284G (huSTING R284G tazCTT), as well as from the wild-type zebrafish STING with the CDN STING agonist (zfSTING WT+ CDN) (see page 276, lines 21-25). However, unlike the wild-type zebrafish STING, which had very high NF-κB signaling, the huSTING R284G tazCTT variant had high type I IFN signaling with much lower NF-κB signaling activity (see pg. 276, lines 25-28). The best ratio of higher type I IFN to lower NF-κB signaling was found with the Tasmanian devil STING variant containing the human STING GOF mutation R284G (tazSTING 4284G) (see pg. 276, lines 28-30).
However, the specification fails to demonstrate that Applicant was in possession of modified STING proteins as described in the claims. Specifically, the specification fails to disclose that Applicant was in possession of modified STING proteins wherein a large genus of first STING protein species CTT is replaced with a large genus of CTT from a second species. Further, the specification fails to demonstrate that Applicant was in possession of the various genera of immunostimulatory bacterium and delivery vehicles as recited in claims 19-23. Additionally, the specification fails to describe the structure of the other genera recited in the claims including the costimulatory proteins/receptors (as recited in claim 27), immunostimulatory proteins that contribute to anti-tumor immunity (as recited in claim 26), proteins that effect/potentiate recruitment/persistence of T cells (as recited in claim 28), TGF polypeptide antagonist (as recited in claim 28), IL-2 modified so that it does not bind to IL-2Ra (as recited in claim 28), IL-2 that has attenuated binding to IL-2Ra (as recited in claim 28), and the other members of the Markush grouping of claim 28.
As currently presented, the specification is directed to a STING variant in which the CTT of human STING was replaced with the CTT of Tasmanian devil STING and that contained the human STING GOF mutation R284G and a S. typhimurium immunostimulatory bacterium. The specification discloses SEQ ID NO: 335 and 336 as possessing the required functions. However, the claims encompass far more than these species. Further, the claims recite the function of these modified STING proteins, delivery vehicles, and immunostimulatory bacterium but does not provide structure. This would represent a large pool of variant proteins, delivery vehicles, and bacterium that must have similar functional activity. Applicant has not described the structure of the genera that is critical to the function. The specification provides limited guidance regarding the structure of the delivery vehicle and immunostimulatory bacterium in the genus of bacteria, while maintaining any given function. See MPEP § 2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
Therefore, these structures are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components.
Thus, the genus of modified STING proteins, delivery vehicles, and immunostimulatory bacterium are broad because the claims recite generic and incompletely described proteins and bacteria. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed proteins and bacteria without adequate descriptions of its component parts or overall makeup. The generically claimed modified STING protein variant in which the CTT of human STING was replaced with the CTT of non-human STING and comprise of one or more amino acid replacements, do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the genus of STING proteins recited in the claims. Similarly, the generically claimed immunostimulatory bacterium comprising modifications whereby TLR2, TLR4, ant TLR5 recognition is reduced, lacks flagella, and comprise penta-acylated lipopolysaccharide, does not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the genus immunostimulatory bacterium. For instance, without knowing the structure of the bacterium, one would not be able to adequately describe the claimed immunostimulatory bacterium. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of proteins and bacterium because, inter alia, the specification does not disclose a correlation between the necessary structure of the protein/bacterium and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed immunostimulatory bacterium may generically describe the bacterium function, it does not describe the immunostimulatory bacterium itself. A definition by function does not suffice to define the genus because it is only an indication of what the modified STING protein/immunostimulatory bacterium does, rather than what it is; therefore it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of modified STING proteins/immunostimulatory bacterium is highly variable (i.e. each STING protein and bacteria would necessarily have a unique structure; see MPEP § 2434), the generic description of the modified STING protein and immunostimulatory bacterium is insufficient to describe the genus.
Further, Applicant has not shown possession of a representative number of species of modified STING proteins and immunostimulatory bacterium. As noted above, the claims are generic for the components of the modified STING proteins and immunostimulatory bacterium. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The claims encompass STING proteins with only 98% sequence homology to SEQ ID NO: 332-336, and any amino acid sequence found in SEQ ID NO: 332-336. These peptides have no correlation between their structure and function. The claims require that the peptide exhibit that constitutively induces type I interferon; has attenuated nuclear factor kappa-light-chain- enhancer of activated B cell (NF-κB) signaling activity compared to the NF-κB signaling activity of human STING; a C-terminal tail (CTT) from a non- human STING protein wherein the non-human STING protein has lower NF-κB signaling activity than human STING; the TRAF6 binding site in the CTT is deleted; comprise portions of STING proteins from two species, whereby the resulting STING protein has constitutive IFN-beta signaling activity, wherein the first species is human, and the second species is selected from among Tasmanian devil, marmoset, cattle, cat, ostrich, boar, bat, manatee, crested ibis, coelacanth, and ghost shark; and confer constitutive activity is/are one or more amino acid replacements selected from replacements that correspond to S102P, V147L, V147M, N154S, V155M, G166E, C206Y, G207E, S102P/F279L, F279L, R281Q, R284G, R284S, R284M, R284K, R284T, R197A, D205A, R310A, R293A, T294A, E296A, R197A/D205A, S272A/Q273A, R310A/E316A, E316A, E316N, E316Q, S272A, R293A/T294A/E296A, D231A, R232A, K236A, Q273A, S358A/E360A/S366A, D231A/R232A/K236A/R238A, S358A, E360A, S366A, R238A, R375A, and S324A/S326A, with reference to the sequence of human STING, as set forth in any one of SEQ ID NOs:305-309, but the specification provides no guidance regarding which variants or fragments are capable of the required function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of SEQ ID NO:335 and 336, the skilled artisan cannot envision the detailed chemical structure of the encompassed STING proteins, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three-dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph).
Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins encompassed by the instant claims (see e.g. page 661, left column).
Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937) teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would reasonably conclude that only SEQ ID NO: 335 and 336, but not the full breadth of the claims, meet the written description provision of 35 USC 112(a).
Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of variant proteins to Applicant. Even if a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form a completely constructed modified STING protein such that one would be able to distinguish it from the polypeptides of the art.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the modified STING protein and immunostimulatory bacterium. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of recombinant proteins as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant respectfully traverses the rejection under 35 USC 112(a) for written description (see pages 35-62 of the Remarks filed 09/10/2025).
Applicant argues the instant application provides more than 5,000 examples of proteins that fall within the scope of the claims; the application provides a list of mutations that result in constitutive activity and provides a list of sequences of non-human STING proteins and of CTTs that have lower NF-κB signaling activity than human STING. The application details at least 3 ways to produce STING proteins that have constitutive activity and NF-κB signaling activity of STING proteins are known and documented in the prior art. No one, however, had thought to combine these properties in order to produce a STING protein that induces and anti-tumor response without inducing an undesirable inflammatory response. The application amply demonstrates possession of the claimed modified STING proteins at the time of the earliest claimed priority date… The application provides lists of mutations in STING that constitutively induce type I IFN, including those that have been identified in patients with interferonopathies, such as SAVI, provides corresponding mutations in non-human STING proteins, and also teaches and exemplifies how to identify other mutations that render its activity constitutive… The encoded STING variants can include a mutation that eliminates a phosphorylation site in STING to reduce NF-κB signaling, or a deletion in the TRAF6 binding site of the CTT to reduce NF-κB signaling… In reading the application, the skilled artisan also can modify a constitutively active variant STING protein, such as a human STING protein or non-human STING protein, to reduce NF-κB signaling activity by eliminating a phosphorylation site in STING… It is within the skill of one of skill in the art to modify a protein, such as by inserting, deleting, or replacing a specific amino acid(s), to achieve a desired effect… Applicant argues that the application describes and claims the types of modifications that result in the claimed properties of the modified STING proteins… it is within the skill of one of skill in the art to generate a modified gene comprising a portion of one gene and a portion of a second gene… it is within the skill of one of skill in the art to employ the modifications described in the application in order to provide a modified STING protein that is modified to constitutively induce type I IFN and that has lower NF-κB signaling activity compared to human STING, and to provide such a modified STING protein in a bacterium or other delivery vehicle.
None of the cited references are relevant to the pending claims; none describe STING, nor a modified STING protein. As demonstrated and described below, the application provides 1) far more than a representative number of species of modified STING proteins; and 2) details of the prior art knowledge of STING and discloses detailed structural features and identifying characteristics, including structural and physical characteristics of the modified STING proteins. The application is considered in view of the high level of skill and knowledge in the art at the time of the earliest claimed priority date regarding the structure and function of STING. This knowledge includes presumptive knowledge of STING, including activation of STING and resulting cellular cascades, the domains thereof and their functions, and the role of STING in diseases. As described in the application, and as known in the art, STING activity/signaling induces type I interferon (IFN) responses; unmodified wild-type STING does so in the presence of ligands, such as cyclic dinucleotides (CDNs; e.g., cGAMP), which are synthesized by host enzyme cGAS in response to sensing cytosolic nucleic acids that result, for example, from infection by a pathogen… the structure and function of the STING protein is known to those of skill in the art, and also detailed in the application. The CTT of the STING protein, an ~40 stretch of amino acids at the C-terminal portion of the protein, and its binding domains are described in the application; see, page 37, line 30, to page 38, line 20… the CTT also contains a TRAF6 binding site; TRAF6 catalyzes the formation of K63-linked ubiquitin chains on STING, leading to the activation of NF-κB. The sequence of the human STING CTT, in addition to the CTT sequence of several non-human species STING proteins including Tasmanian devil, marmoset, cattle, cat, ostrich, boar, bat, manatee, crested ibis, coelacanth, zebrafish, ghost shark, and mouse, also is shown in the application (see, the table on pages 38-39). As described in the application, it is known in the art that STING proteins from different species exhibit different levels of NF-κB signaling activities… thus it was known in the art prior to the priority date of the application, and described in the application, the structure and role of STING protein at the cellular level, as well as the results of overactive STING, and known modifications at the genetic level that contribute to overexpression and constitutive induction of type I IFN.
In addition to the extensive knowledge and understanding of the art, the application details the structure and functioning of STING and describes methods to render its activity in inducing type IIFN constitutive, and methods for reducing NF-kB signaling activity. The application describes how to apply these methods to human STING proteins and non-human STING proteins, and provides the sequences of exemplary non-human STING proteins, including the CTT portions thereof. The following discussion includes excerpts from the application describing exemplary ways of generating modified STING proteins that are modified so that induction of type I IFN is constitutive, and activation of the NF-κB signaling pathway is reduced. The application provides working examples (Examples 20-28, and detailed description throughout the application) demonstrating identification of mutations that confer constitutive activity, and also identifies exemplary corresponding modifications in non-human STING proteins. Example 20 teaches how to identify gain-of-function mutations in any of the cytosolic DNA/RNA sensor proteins… and provides lists of exemplary mutations, and shows constitutive expression of type I IFN is induced upon expression of the encoded proteins in cells infected with the bacteria… in reading the application, the skilled artisan can select a STING protein from a non-human species that has reduced NF-κB signaling activity compared to human STING and modify the protein to have constitutive signaling are exemplified in the application, and corresponding modifications in non-human species also exemplified (see, the tables on pages 271-273). Alternately, in reading the application, the skilled artisan would understand that creating a chimeric STING protein comprised of a STING protein from a first species with a modification that results in constitutive activity and where the CTT is replaced with the CTT of a STING protein from a second species that has lower NF-κB signaling activity than human STING results in a STING with the claimed properties (see, claim 2). Methods of gene editing were well known in the art well prior to the earliest priority date of the application. The application sets for the sequences of STING from several exemplary non-human species, and also sets forth the sequences of the CTT of the exemplary non-human STING sequences. It is within the skill of a person skilled in the art to replace a portion of a gene with a portion of another gene. The person skilled in the art in reading the application understands how to replace the CTT in a STING protein from a first species with the CTT of a STING protein from a second species that has lower NF-κB signaling activity than the first species; the person skilled in the art could further introduce a constitutive mutation in such a chimeric STING.
The instant modified STING proteins are not defined by their functions, but their properties with respect to the wild-type proteins and with respect to known modifications in known sequences. The modified protein is defined by the modifications that enhance or attenuate the functions of the wild-type protein. The claimed modified STING has constitutive activity in inducing type I IFN expression and also has lower NF-B signaling activity; these effects are a result of modifications in known structural areas of STING, and such modifications are described in the application. The application provides lists of mutations in STING that constitutively induce type I IFN, including those that have been identified in patients with interferonopathies, such as SAVI, provides corresponding mutations in non-human STING proteins, and also teaches and exemplifies how to identify other mutations that render its activity constitutive. Such modifications can be introduced into a human or non-human STING protein using methods known to those of skill in the art. As described in the application, the claimed modified STING proteins can be generated by, for example: (1) selecting a non-human STING that has lower NF-KB signaling activity and introducing a constitutive modification; (2) generating a chimeric STING with a CTT from a species with lower NF-B signaling activity than human STING, and rendering the STING constitutively active; (3) eliminating a phosphorylation site to lower NF-kB signaling activity in a STING protein that has a modification whereby it is constitutively active; and (4) deleting the TRAF6 binding site. These modifications are described in the application, and all of the constitutive modifications are known in the art, as are the sequences of non-human STING proteins and their CTT sequences. See Erfindergemeinschaft UroPep GbR v. Eli Lilly & Co., 276 F. Supp. 3d 629, 648 (E.D. Tex. 2017) ("[W]hen a genus is well understood in the art and not itself the invention but is instead a component of the claim, background knowledge may provide the necessary support for the claim."). See also In re Herschler, 591 F.2d 693 at 701 (CCPA 1979) (finding adequate written description for concurrently administering a steroidal agent and a novel DMSO solvent when the specification disclosed only one steroidal agent" noting "[w]ere this application drawn to novel 'steroidal agents,' a different question would be posed."). In this instance, there, thus is extensive knowledge in the art regarding STING proteins from numerous species, knowledge of the structure and function of STING proteins, and identification of mutations that confer constitutive activity; and the NF-KB signaling activity of many species and its locus in the CTT. The application provides sequences of STING proteins, identification mutations, and teaches how to reduce NF-KB signaling activity… All claims require a modified STING protein that: (1) is modified to have constitutive activity, whereby expression of type I interferon (IFN) is constitutive; and (2) has lower NF-KB signaling activity compared to that of an unmodified human STING protein. The application describes lists of exemplary modifications of human STING that result in a protein that constitutively induces type I IFN and corresponding exemplary modifications in non-human species, and also describes that chimeric STING proteins, comprising a modification whereby the protein constitutively induces type I IFN and comprising a CTT from a species that has lower NF-KB signaling compared to human STING, demonstrate enhanced type I IFN induction to NF-KB signaling ratio. The application also describes methods for reducing NF-KB signaling activity in STING variants, including constructing a chimera with a CTT from a species with low NF-KB signaling activity, and eliminating a phosphorylation site in the STING protein or deleting the TRAF6 binding site to reduce NF-KB signaling. As discussed above, modifying STING to have constitutive activity and to have lower NF-KB stimulating activity compared to human STING exploits the immune system of the host to increase the anti-tumor response, but to not, by virtue of employing a STING protein with low NF-kB activity, induce an undesirable inflammatory response.
Thus, the specification clearly conveys to those of skill in the art that at the time of the earliest claimed priority date of the instant application, Applicant was in possession of that which is claimed. The application provides 1) more 500 examples of proteins within the scope of the claims and provides far more than a representative number of species falling within the genus, and, notwithstanding that, discloses structural features and identifying characteristics, including structural and physical characteristics, functional characteristics coupled with known or disclosed correlation with structural characteristics or a combination of such factors demonstrating that Applicant was in possession of the claimed subject matter and invented what is claimed. MPEP § 2163; see University of California v. Eli Lilly, 119 F. 3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997) and Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co. 560 F.3d 1366 (Fed. Cir. 2009).
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive.
Examiner respectfully disagrees with Applicant’s assertion regarding written description of the invention. The base claim is incredibly broad and only describes the STING protein by function. While the specification may provide examples of proteins that fall within the scope of the claims, these are merely exemplary and the claims are not limited to these examples. Furthermore, while Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the modified STING protein, but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents/components. For example, the modified STING protein is defined by its function of inducing production of type I IFN and lowered activation of NF-kB signaling pathway compared to human STING, and the modified STING proteins are also defined by their ability to promote an interferonopathy. Additionally, the modified STING protein is described by being a modified non-human STING, a chimeric STING protein comprising a first species STING protein with replacement of the CTT from a second species STING protein, or either one with the TRAF6 binding site deleted. In both the base claims and the dependent claims, for at least one agent/component in each claim, the claims only describe what the agent/component does, not what the agents/components are. While the agent/component of modified STING protein, wherein the STING protein is a chimera, that comprises the replacing CTT of species recited in claim 11 is described as long as there are no additional functional requirements like those found in the dependent claims, the first species is not defined in any way, except for its functional properties. Even when given possible sequences from which to select a fragment of a peptide that would make up the modified STING protein, the question remains about which one(s) of the encompassed peptides would actually make the complete structure of the modified STING. While methods to identify the peptides with the required function may be routine in the art, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that applicant has not sufficiently described the claimed subject matter.
There are thousands of possible modified STING proteins encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has supplied a few species of modified STING proteins, such as Tasmanian devil and ostrich, some of which are not included in the sequences of the instant claims and may comprise variants thereof of these sequences. Further, the claims are not limited to this species. The claims encompass all modified STING proteins that can induce production of type I IFN and has lowered activation of the NF-kB signaling pathway compared to human STING. This encompasses an extremely broad genus of peptides with a specific function, for which no correlating structure is provided. While one of skill in the art could likely screen for said peptides and antibodies, the mere fact that experimentation is necessary to identify the members of the genus indicates that proper description has not been provided.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene' s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of STING proteins. In the instant application, neither the art nor the specification provide a sufficient representative number of modified STING proteins or a sufficient structure-function correlation to meet the written description requirements.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Further, arguments relating to the isolation of an antibody with specific characteristics may be more appropriately directed to the invention' s enablement, since the method of isolating would detail how to make the invention. However, the enablement of the invention has not been rejected by the Examiner.
Regarding the disclosed species, Applicant is attempting to read limitations into the claims that are not present. As indicated in MPEP 2145, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims are not limited to the modified STING proteins described in the arguments, and instead encompass a large genus of proteins, for which the components are not adequately described.
Examiner acknowledges that the cited references do not specifically describe STING, however, the references describe the unpredictability of protein biochemistry and highlight the importance of fully describing the structure of proteins in order to determine its correlating function. For example, Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column). Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, large efforts are still required to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins encompassed by the instant claims (see e.g. page 661, left column). Thus, the references further support that proper written description is needed when claiming proteins because the function of these biomolecules is dependent on its structure.
Furthermore, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims do not specify that the modified STING protein must be of human origin or that the proteins are limited to the species recited in the specification. As stated above, the claims encompass a large genera of modified STING proteins even other non-human STING proteins. This is also true for the claimed immunostimulatory bacterium recited in the claims. The claims are not limited to the claimed immunostimulatory bacterium disclosed in the specification and Applicant has not demonstrated possession of various immunostimulatory bacterium as claimed.
Applicant must recite in the claims the novelty of their invention and that they were in possession of it. Further, with respect to the cases Applicant mentioned in their argument (i.e., Erfindergemeinschaft UroPep GbR v. Eli Lilly & Co., 276 F. Supp. 3d 629, 648 (E.D. Tex. 2017) and In re Herschler, 591 F.2d 693 at 701 (CCPA 1979)), these cases are not applicable to this current case. The Erfindergemeinschaft case is drawn to phosphodiesterase inhibitors for the treatment of prostatic diseases. The claims recite “selective PDE5 inhibitors” which was argued that this limitation lacked written description. However, it was determined to be fully described because the court found that the specification disclosed of 10 discrete compounds and two classes of compounds with common structural features. Therefore, there is sufficient written description because one of skill in the art can envision what is encompassed by the term “selective PDE5 inhibitors”. In the Herschler case, the courts found there was adequate written description for “steroidal agent” although there was only one example listed in the specification because there is extensive knowledge regarding “steroidal agents” in the art and the invention was not drawn to a novel steroidal agent. These cases are distinguished from the instant case because the present issue is that the claimed modified STING proteins can be anything as long as it induces production of type I IFN and lowers activation of the NF-kB signaling pathway compared to human STING. This encompasses, non-human STING, chimeric STING, mutated human STING, etc. that Applicant has not demonstrated possession of the modifications and they are not sufficiently described. Further, there are several issues with regard to Applicant’s arguments that the specification discloses 5000-6000 embodiments in the specification, and that these embodiments would be sufficient to support adequate written description. First, Applicant is relying on limitations that are not actually recited in the claims. As stated in MPEP 2145, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Second, Applicant is failing to acknowledge the extremely large size of the encompassed genus. For example, the claims are not limited to the dozen STING proteins identified in Applicant’s remarks. In fact, the specification specifically states that “The human TMEM73 gene is characterized by significant heterogeneity and population stratification of alleles” (see specification page 124). This indicates that even the parent protein sequences are highly variable, which as indicated by the references above, contributes to unpredictability in protein structure after mutation. Furthermore, claim 1 recites “the STING protein comprises amino acid modifications …comprise one or more of an amino acid insertion, deletion, and replacement”. This extraordinarily broad language that encompasses essentially any modification to the protein at any residue location or protein segment. To give an idea of the vastness of the encompassed genus, isoform 1 of human STING of NCBI accession NP_938023.1 is 379 amino acids long. Choosing even 2, 3, or 4 mutation sites within this single protein would result in 71,000, 9 million and 846 million combinations. Given that any residue or protein segment could be added, deleted, or mutated, and as Applicant has conceded, there are a large number of parent proteins from which the sequence may be altered, there are billions of possible proteins encompassed by the instant claims. While the prior art has disclosed some embodiments that fall within the instant claimed genus, such as Konno et al. (previously submitted) teach that gain of function mutation of STING R284S that exhibits constitutive activity (see Abstract) and disclose of other mutations that occurs in an interferonopathy including C206Y and R284G (see Introduction, 4th para.), and even with the limited number of possible mutation sites and a set of possible parent proteins provided by Applicant, the claimed invention is not adequately described. Even if there are potentially thousands of proteins that can be created from the limited exemplary parent proteins and mutation sites, these embodiments have highly related structures, and therefore are not representative of the extremely large genus encompassed by the claims. Further, it cannot be assumed that every embodiment, or a significant portion, of the encompassed embodiments will function as claimed nor are the claims limited to these species disclosed in the specification. As stated above, the references cited in the rejection describe the unpredictability of protein biochemistry and highlight the importance of fully describing the structure of proteins in order to determine its correlating function. In this particular case, it cannot be assumed that every embodiment potentially encompassed in the specification would function as claimed simply due to the nature of proteins and their inherent unpredictability.
As such, the written description rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17/590,700
Claims 1-28, 30-34, and 38-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-26 and 28-44 of copending Application No. 17/590,700 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘700 claims are drawn to a modified STING protein comprising amino acid modifications wherein each modification results in a STING protein that induces constitutive expression of type I interferon; the modifications are insertions, deletions, and/or replacements of amino acids (see all claims). The ‘700 claims are drawn to a modified STING protein wherein the protein also has lower NF-κB signaling activity compared to the NF-κB signaling activity of human STING (see all claims). The ‘700 claims are drawn to a chimera that comprises a human STING protein (SEQ ID NO: 305 of both applications share 100% identity) in which the CTT region is replaced with the CTT from a non-human STING protein that has a lower NF-κB signaling activity than the NF-κB signaling activity of human STING; particularly, the non-human STING CTT portion is from Tasmanian devil STING (SEQ ID NOs: 371 and 349 of the reference application share 100% identity with SEQ ID NO: 353 of the present application) (see claims 19-20 and 39-41). The modified human STING protein with a CTT from Tasmanian devil comprising SEQ ID NO: 397 of the reference application shares 99.7% identity with SEQ ID NO: 336 of the present application. The amino acid modifications in the STING protein that confer constitutive activity comprise the following replacement(s): S102P, V147L, V147M, N154S, V155M, G166E, C206Y, G207E, S102P/F279L, F279L, R281Q, R284G, R284S, R284M, R294K, R284T, R197A, D205A, R310A, R293A, T294A, E296A, R197A/D205A, S272A/Q273A, R310A/E316A, E316A, E316N, E316Q, S272A, R293A/T294A/E296A, D231A, R232A, K236A, Q273A, S358A/E360A/S366A, D231A/R232A/K236A/R238A, S358A, E360A, S366A, R238A, R375A, and S324A/S326A (see claim 42). The ’700 claims are drawn to a pharmaceutical composition comprising the modified STING protein in a pharmaceutically acceptable vehicle (see claims 29 and 30). The ‘700 claims are drawn to an immunostimulatory protein that confers or contributes to anti-tumor immunity in a tumor microenvironment (see claims 17 and 18). The ‘700 claims are drawn to an immunostimulatory protein comprises a cytokine (see claim 21). The ‘700 claims are drawn to an immunostimulatory protein is IL-15/IL-15R alpha chain complex (see claim 20). The ‘700 claims are drawn to a delivery vehicle which is an exosome, a nanoparticle, a liposome, a bacterium, a cell, or a virus (see claim 32).
The difference between the instant claims and the ‘700 claims is that the ‘700 claims are drawn to amino acid modifications that confer constitutive activity that correspond to those associated with the auto-inflammatory disease STING-associated vasculopathy with onset infancy (SAVI). However, according to MPEP § 804(II)(B)(1), examiner must construe claim 12 of reference application ‘700 to determine what the claim covers. To do this, examiner can review the specification of the reference application to see which embodiments are disclosed. The specification of the ‘700 application disclose that SAVI is a type I interferonopathy disorder comprising the following mutations: V147M, N154S, V155M, G166E, C206Y, R281Q, R284G, and S102P/F279L (see pgs. 139-141). Furthermore, the specification teach that the term “combination” refers to any association between or among two or more items…the elements of a combination are generally functionally associated or related (see pgs. 68-69). Thus, the combination recited in the reference claims could also include an immunostimulatory bacterium under the broadest reasonable interpretation. The specification discloses that the immunostimulatory bacterium can be a strain of Salmonella, Rickettsia, Vibrio, Klebsiella, Bordetella, Neisseria, Aeromonas, Francisella, Corynebacterium, Citrobacter, Chlamydia, Haemophilus, Brucella, Mycobacterium, Mycoplasma, Legionella, Rhodococcus, Pseudomonas, Helicobacter, Bacillus, or Erysipelothrix (see pg. 33, lines 24-34). The specification also discloses that the immunostimulatory bacterium comprise penta-acylated lipopolysaccharide, msbB-/pagP-, lacks flagella, and can be adrA-, purI-, pagP-, msbB-, and csgD- (see pgs. 4-6). Therefore, the ‘700 claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments
Applicant respectfully traverses the (provisional) double patenting rejections (see pages 73 and 74 of the Remarks filed 09/10/2025).
In regard to the provisional rejection of 17/590,700, Applicant argues that there can be no obviousness-type double patenting in the first application to issue; this application is years ahead of the copending application. The instant application has been in prosecution for several years; a response to a non-final Office Action was filed in the '700 application on July 14, 2025. Applicant thus defers resolution of this issue until there is allowable subject matter in one of the applications. If this application is allowed first, a terminal disclaimer is not needed.
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive.
As stated in the previous action, Examiner acknowledges the filing dates of the present and copending applications. However, Applicant is reminded that a copending application in a double patenting rejection need not be considered prior art (i.e., filed earlier) in order for a terminal disclaimer to filed (see MPEP 804.01). In this particular case, the present application is filed earlier than the ‘700 application. Additionally, simply because the present application has been in prosecution for several years, whereas the ‘700 application submitted a non-final Office Action this year, one cannot assume that the present application will be found allowable first.
Additionally, the Examiner acknowledges that MPEP 1490 states that if the provisional ODP rejections in both applications are the only rejections remaining in those applications, the examiner should then withdraw the provisional ODP rejection in the earlier-filed application thereby permitting that application to issue without need of a terminal disclaimer. The instant application has a filing date of 01/11/2022, while the copending application has a filing date of 02/01/2022. The instant application is therefore the earlier filed application. Further, the double patenting rejection is not the only rejection remaining, and therefore the rejection is maintained.
Applicant is reminded that a rejection under double patenting precludes the identification of allowable subject matter. Applicant has not filed a terminal disclaimer, and the claims remain rejected for reasons set forth above. As such, the ‘700 application anticipates the present claims. Also, whether the copending application is presently under prosecution does not change the fact that the claims as currently presented overlap in scope with the present application and a terminal disclaimer is required.
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As such, the double patenting rejection is maintained.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-18 and 38-43, effective filing date of 01/16/2020 for all claims except claim 1, are rejected under 35 U.S.C. 103 as being unpatentable over Barber (WO 2019/035901 A9; publication date: 02/21/2019) and further in view of Fisher et al. (US 2020/0149053 A1, priority date of 07/12/2017 which predates instant application effective filing date of 02/27/2019; previously submitted), Miller et al. (PNAS 108(3): 12348-12353, publication date: 07/26/2011; previously submitted), and de Oliveira Mann et al. (2019, Cell Reports 27, 1165–1175; previously submitted).
With respect to instant claims 1, 6, 15, 16 and 18, Barber discloses of constitutively active STING mutants to stimulate an immune response in a patient (see Abstract). Particularly, Barber discloses that the claimed STING mutants comprise either an N154S or R284S mutation (see claims 5, 26, 31, and 33; [0008]; [0009]; [0018]; [0020]; Example 1). Further, Barber discloses that V147L/M, N154S, V155M, C206Y, R281Q, R284G, and S102P/F279L mutations exert a gain-of-function phenotype referred to as SAVI (see [0006]). Barber does not explicitly disclose of the sequence of the mutated STING, but this mutation was in reference to human STING (see [0054]). Thus, one of ordinary skill would expect a ~98% match to instant SEQ ID NOs: 305-307 as the STING-R284S or H154S variants of Barber are singular mutations of the human STING.
Barber fails to teach that the STING mutants lower NF-ĸB signaling pathway as claimed in the present claims. This is remedied by Miller et al. and de Oliveira Mann et al.
Further, Barber fails to teach of a pharmaceutical composition as described by claim 38. This is remedied by Fisher et al.
With respect to instant claims 2-5, 7-14, 17, and 39-43, De Oliveira Mann et al. teach of a modular architecture of the STING CTT that allows interferon and NF-κB signaling adaptation (see entire document). Particularly, de Oliveira Mann et al. disclose of a chimeric human STING protein wherein the CTT tail is substituted with the CTT of zebrafish (see Abstract; p. 1167, col. 1). Although this chimera resulted in enhanced activation of NF-κB signaling (see p. 1167, col. 1; Fig. 1C), de Oliveira Mann et al. disclose the properties of several different species and their STING proteins (see Fig. 1A). Particularly, Fig. 1A displays the STING proteins of animals (such as marmoset, cattle, bat, boar, cat, manatee, Tasmanian devil, crested ibis, coelacanth, and ghost shark) that induce type I IFN and attenuates NF-κB signaling compared to the NF-κB signaling of the human STING. While de Oliveira Mann et al. does not disclose the sequence of the Tasmanian devil STING protein, Miller et al. teach of the whole genome sequencing project of the Tasmanian devil (see Abstract). The Tasmanian devil STING protein in Miller et al. shares 100% identity to SEQ ID NO: 331 (see alignment).
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Additionally, in regard to claim 11, the CTT portion of the Tasmanian devil STING protein is also disclosed in Miller et al. that shares 100% identity with SEQ ID NO: 353 (see alignment; amino acid residues 339-381 of SEQ ID NO: 331).
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In regard to claims 12, 40 and 41, de Oliveira Mann et al. teach that the role of TRAF6 in human STING signaling is non-essential (see p. 1168, col. 2; Fig. 3C). Particularly, de Oliveira Mann et al. highlights the signaling motifs for IRF3, TBK1, and NF-κB signaling and indicates the amino acid sequence DFS located downstream of the TBK1 signaling motif in human STING plays no role in boosting NF-κB signaling as it does not comprise the PxExxD motif which shares similarity to the tumor necrosis factor receptor-associated factor (TRAF) binding sites (see pg. 1168; Fig. 2).
Lastly, with respect to instant claim 38, Fisher et al teach of genetically programmed microorganisms for the treatment of cancer (see Abstract). Fisher teaches that their microorganisms can encode immune initiators including agonists of STING (immunostimulatory) (see [0011]-[0012]). The STING agonists can include antibodies (proteins) (see [0011]-[0013]). Fisher teaches that STING is part of the cytosolic DNA sensing pathway (see [0405]). STING activation leads to production of type 1 interferon (see [0405]). Fisher et al. teach that the engineered bacteria can comprise a pharmaceutically composition with a carrier (vehicle) (see [0306]).
As such, it would have been obvious to one of ordinary skill in the art at the time of the present invention to modify the teachings of Barber to develop a modified chimeric STING protein comprising a human STING protein with a substituted non-human CTT, i.e. Tasmanian devil CTT, that has lower NF-κB signaling activity than human STING further comprising mutation(s) that occurs in an interferonopathy aligned with the human STING protein with a deleted TRAF6 binding site. One would be motivated to do so because Barber teaches that the N154S and R284S variants constitutively activate IFN (see Example 1, [0121]). Additionally, one would be motivated to add interferonopathy-related mutations, such as V147L/M, V155M, C206Y, R281Q, R284G, or S102P/F279L to the N154S and R284S STING protein sequence as these are known mutations that constitutively induce type 1 interferon. With respect to reducing NF-κB signaling activity, de Oliveira Mann et al. disclose of building a chimeric human STING protein wherein the CTT of the human STING protein is replaced with a non-human CTT. While the Tasmanian devil STING protein was not used in the construction of building this chimera, de Oliveira Mann et al. disclose that the Tasmanian devil STING protein induces type I interferon and attenuates NF-κB signaling activity compared to the NF-κB signaling activity of human STING. Ultimately, a chimeric STING protein comprising the N154S and R284S variants of human STING protein (of Barber) with a substituted Tasmanian devil CTT (SEQ ID NO: 353) would result in at least 98% sequence identity to SEQ ID NO: 336 of instant claims 17 and 42. The combination of these known sequences and mutations would produce a chimeric STING protein that constitutively induces type I interferon and has attenuated NF-κB signaling activity compared to the NF-κB signaling activity of human STING with a predictable level of success. Further, as explained by de Oliveira Mann et al., the TRAF6 binding site of the human STING protein plays a non-essential role so a TRAF6 deletion represents an obvious variation.
Lastly, it would have been obvious to one of ordinary skill in the art at the time of the present invention to develop a pharmaceutical composition comprising the modified STING protein disclosed by Barber as it would allow for the modified STING protein to be more stable, due to the pharmaceutical carrier, making it beneficial to medical professionals to easily administer the claimed modified STING protein to their patients.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674